Extracellular deposition of the amyloid [unreadable]-protein (A[unreadable]) in brain is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Cerebral parenchymal A[unreadable] deposition can occur as diffuse plaques, with little surrounding pathology, or as fibrillar plaques associated with dystrophic neurons and inflammation. Fibrillar A[unreadable] deposition in the cerebral vasculature, a condition known as cerebral amyloid angiopathy (CAA), is also commonly found in Alzheimer's disease. Additionally, several familial monogenic forms of CAA exist that result from mutations that reside within the A[unreadable] peptide sequence of ASPP gene including Dutch- type (E22Q) and Iowa-type (D23N) which cause early and severe cerebral vascular amyloid deposition. Recent studies have implicated cerebral microvascular AS deposition in promoting neuroinflammation and dementia in patients with CAA. Cerebral microvascular, but not parenchymal, amyloid deposition is more often correlated with dementia in individuals afflicted with Alzheimer's disease and CAA. Neuroinflammation remains a viable target for the treatment of amyloid-depositing diseases in the central nervous system, particularly the neuroinflammation associated with cerebral microvascular amyloid. Recently, we generated novel transgenic mice that express human vasculotropic Dutch/Iowa mutant human amyloid B-protein precursor (ASPP) in brain, designated Tg-SwDI, that develop early-onset and robust fibrillar cerebral microvascular A[unreadable] deposition in the absence of parenchymal fibrillar plaque amyloid. More recent work from our laboratory has demonstrated that Tg-SwDI mice exhibit neuroinflammation that is strongly associated with the cerebral microvascular amyloid deposition. Furthermore, Tg-SwDI mice show marked deficits in behavioral performance. In light of these findings, the overall hypothesis that forms the basis for this proposal is that cerebral microvascular fibrillar AB deposition promotes neuroinflammation and behavioral deficits in the absence of fibrillar plaque amyloid. In the present proposal, we plan to thoroughly characterize the microvascular amyloid and the neuroinflammatory response, as well as investigate the effects of anti-inflammatory drug treatment on modulating microvascular amyloid, neuroinflammation, and behavioral decline in Tg-SwDI mice, a novel and unique transgenic model that only develops microvascular fibrillar A[unreadable] deposition. Completion of these studies should provide important insight into microvascular amyloid-mediated neuroinflammation and dementia that is an understudied and likely important, aspect of disorders that involve CAA. Additionally, since CAA pathology is commonly found in Alzheimer's disease this pathologic target may have far reaching implications in combined treatment strategies for this neurodegenerative condition and its related CAA disorders.